Intravenous ferric derisomaltose versus saccharated ferric oxide for iron deficiency anemia associated with menorrhagia: a randomized, open-label, active-controlled, noninferiority study.

A multicenter, randomized, open-label, phase III study was conducted to compare the efficacy and safety of intravenous ferric derisomaltose (FDI) versus saccharated ferric oxide (SFO) in Japanese patients with iron deficiency anemia associated with menorrhagia. FDI can be administered as a single dose up to 1000 mg, whereas SFO has a maximum single dose of 120 mg. The primary endpoint, which was the maximum change in hemoglobin concentration from baseline, was noninferior for the FDI group compared with the SFO group. The incidence of treatment-emergent adverse events was lower in the FDI group (66.2%) than in the SFO group (90.8%). Notably, the incidence of serum phosphorus level < 2.0 mg/dL was significantly lower in the FDI group (8.4%) than in the SFO group (83.2%), and severe hypophosphatemia (≤ 1.0 mg/dL) occurred in 6.7% of SFO­treated patients compared with none in the FDI group. The percentage of patients who achieved the cumulative total iron dose during the 8-week treatment period was higher in the FDI group (92.8%) than in the SFO group (43.2%). The study met its primary endpoint, and also demonstrated the tolerability of a high dose of FDI per infusion, with a lower incidence of hypophosphatemia.

[Myelodysplastic syndromes and iron metabolism].

Myelodysplastic syndromes (MDS) are clonal hematopoietic disorders characterized by ineffective hematopoiesis in bone marrow and cytopenias in peripheral blood. In patients with MDS, iron overload is frequent due to red blood cell transfusions and ineffective erythropoiesis. Dysplastic erythroblasts in MDS secrete humoral factors such as erythroferrone, which suppress hepatic expression of hepcidin. Hepcidin is the key regulator of systemic iron homeostasis, and suppression of hepcidin expression leads to an increase in iron absorption from the intestines, exacerbating systemic iron overload. Patients with MDS with ring sideroblasts (MDS-RS) are prone to iron overload, with most harboring splicing factor 3B subunit 1 (SF3B1) mutations in hematopoietic cells. SF3B1 mutations may induce ring sideroblasts by downregulating ATP binding cassette subfamily B member 7, which exports iron-sulfur clusters from the mitochondria to the cytoplasm. Iron overload in MDS causes hepatic dysfunction, diabetes, cardiac failure, and atherosclerosis, whereas excess iron may suppress normal hematopoiesis. Though randomized control studies are lacking, results from retrospective and cohort studies indicate that iron chelation therapy is appropriate for lower-risk MSD patients with transfusion-related iron overload, although it is not recommended for higher-risk MSD patients with short life expectancy.

Progress in iron metabolism research.

Iron is essential for various cellular processes, but an excess of iron may cause organ damage through the production of reactive oxygen species. Therefore, the amount of iron in the body must be strictly controlled. The central regulator of systemic iron homeostasis is hepcidin, which is primarily produced in the liver. Various molecules, including HFE, transferrin receptor 2 (TFR2), and hemojuvelin (HJV), are involved in sensing systemic iron status. Hepatocytes produce hepcidin in response to excess iron and inflammatory stimuli (e.g., interleukin-6), whereas hepcidin expression is downregulated by hypoxia, anemia, and erythropoietic activity. In mice, erythroferrone, secreted from erythroblasts, suppresses hepcidin expression. Hepcidin downregulates the protein expression of ferroportin, the only iron exporter in mammalian cells, and thereby downregulates iron absorption from intestine and iron release from macrophages. Mutations in the genes HFE, TFR2, HJV, HAMP (encoding hepcidin), and SLC40A1 (encoding ferroportin) cause hereditary hemochromatosis, whereas mutations in TMPRSS6 (which encodes matriptase 2) cause iron-refractory iron deficiency anemia through the upregulation of hepcidin expression. In chronic anemias, such as ß-thalassemia, myelodysplastic syndromes, and aplastic anemia, repeated red blood cell transfusion can cause systemic iron overload. Iron chelation therapy improves the prognosis of patients with such conditions.

[Iron-refractory iron deficiency anemia].

The major causes of iron deficiency anemia (IDA) include iron loss due to bleeding, increased iron requirements, and decreased iron absorption by the intestine. The most common cause of IDA in Japanese women is iron loss during menstruation. Autoimmune atrophic gastritis and Helicobacter pylori infection can also cause IDA by reducing intestinal iron absorption. In addition to these common etiologies, germline mutations of TMPRSS6 can cause iron-refractory IDA (IRIDA). TMPRSS6 encodes matriptase-2, a membrane-bound serine protease primarily expressed in the liver. Functional loss of matriptase-2 due to homozygous mutations results in an increase in the expression of hepcidin, which is the key regulator of systemic iron homeostasis. The serum hepcidin increase in turn leads to a decrease in iron supply from the intestine and macrophages to erythropoietic cells. IRIDA is microcytic and hypochromic, but decreased serum ferritin is not observed as in IDA. IRIDA is refractory to oral iron supplementation, but does respond to intravenous iron supplementation to some extent. Because genetic testing is required for the diagnoses of IRIDA, a considerable number of cases may go undiagnosed and may thus be overlooked.

A Japanese family with X-linked sideroblastic anemia affecting females and manifesting as macrocytic anemia.

X-linked sideroblastic anemia (XLSA) is a rare hereditary disorder that typically manifests in males as microcytic anemia. Here, we report a family with XLSA that affects females and manifests as macrocytic anemia. The proband was a Japanese woman harboring a heterozygous mutation c.679C>T in the ALAS2 gene. This mutation causes the amino acid substitution R227C, which disrupts the enzymatic activity of erythroid-specific δ-aminolevulinic acid synthase. The mutation was not detected in the ALAS2 complementary DNA from peripheral blood red blood cells of the proband, indicating that the cells were mostly derived from erythroblasts expressing wild-type ALAS2. The proband's mother, who had been diagnosed with myelodysplastic syndrome, also had XLSA with the same mutation. Clinicians should be aware that XLSA can occur not only in males but also in females, in whom it manifests as macrocytic anemia.

Iron chelation therapy with deferasirox induced complete remission in a patient with chemotherapy-resistant acute monocytic leukemia.

BACKGROUND: A patient with chemotherapy-resistant acute monocytic leukemia who achieved complete remission (CR) after iron chelation therapy (ICT) with deferasirox is reported for the first time. A 73-year-old Japanese man with acute monocytic leukemia who was refractory to conventional remission induction chemotherapies achieved a partial response, with some improvement of his hemoglobin level and white blood cell count after gemtuzumab ozogamicin (GO) treatment. Seven months after GO treatment, the disease relapsed and the patient developed pancytopenia. He declined further chemotherapy, and started receiving 1,200-1,800 ml of packed red blood cell transfusion per month together with ICT with deferasirox (baseline serum ferritin level was 1,412 ng/ml). Twelve months after the initiation of deferasirox, the patient's serum ferritin level decreased to below 1,000 ng/ml and deferasirox was discontinued. Four months after discontinuation of deferasirox, the blood cell count normalized and the patient became transfusion-independent. Bone marrow aspiration and biopsy revealed hematological and cytogenetic CR. CONCLUSION: CR was achieved after ICT with deferasirox in a patient with acute myelogenous leukemia, suggesting that deferasirox may have an antileukemic effect in the clinical setting.